We measured changes in brain magnetization transfer ratio (MTR) as a potential indicator of myelin density in brain tissue of patients with relapsing-remitting multiple sclerosis (RRMS) treated with delayed-release dimethyl fumarate (DMF) in the Phase 3 DEFINE study. DEFINE was a randomized, double-blind, placebo-controlled study in which patients with RRMS were randomized 1:1:1 to 2 years of treatment with delayed-release DMF 240 mg twice daily (BID) or three times daily (TID) or placebo. MTR was analyzed in whole brain and normal-appearing brain tissue (NABT) at baseline, week 24, 1 year, and 2 years in a subset of patients. MTR data from 392 patients were analyzed. Mean percentage reduction from baseline to 2 years in median whole brain MTR was -0.386 % in the placebo group vs increases of 0.129 % (p = 0.0027) and 0.096 % (p = 0.0051) in the delayed-release DMF BID and TID groups, respectively. Similarly, mean percentage reduction from baseline in median NABT MTR was -0.392 % with placebo vs increases of 0.190 % (p = 0.0006) and 0.115 % (p = 0.0029) with delayed-release DMF BID and TID, respectively. Post hoc analysis of data from patients with no new or enlarging T2 lesions (n = 147), or who experienced no relapses (n = 238), yielded similar results. In this analysis, increases in MTR in brain tissue most likely reflect increases in myelin density in response to delayed-release DMF. These data in patients with RRMS are consistent with preclinical studies that indicate a potential for cytoprotection and remyelination with delayed-release DMF treatment.

Magnetization transfer (MT), refers to the transfer of longitudinal magnetization from the hydrogen nuclei of water that has restricted motion to the hydrogen nuclei of water that moves with many degrees of freedom. Yep it is difficult to understand what this means, but it is suggested that MTR can detect myelination and importantly remyelination. Therefore the inference from this study is that BG-12 is promoting remyelination as the MTR signal increased compared to baseline whereas in the placebo group demyelination continued. So have we entered the age of repair already? Maybe. However, MRI parameters have notoriously shown poor correlates with histology in the tissues. At present, MTR and Diffusion Tensor Imaging measures probably offer the most realistic and feasible outcome measures for detecting remyelination, no one measure currently demonstrates sufficiently high sensitivity or specificity to myelin. However we know that BG-12 (tecfidera) can inhibit the inflammatory response and if you do this it can allow the natural repair mechanisms to do their job and repair and so are changes in MTR special for BG-12, well they have been seen with other DMT. So is the best remyelination strategy just ensuring that the inflammatory response is controlled. This is what happened in pre-clinical models such as EAE....no inflammatory response = no demyelination & nerve loss. However reports in demyelinating models such a cuprizone did not show remyelination. So maybe the message is get rid of inflammation and repair will follow. Again optimal effects would be seen the earlier you start as there are more nerves left to repair and more myelinating precursors to repair.